The first step in virus replication is entry. The mechanisms used by poxviruses are complicated by the existence of two distinct infectious forms with different external membranes. Another complicating factor is the ability of vaccinia virus to enter cells through the plasma membrane and by endocytosis. We have identified a complex comprised of at least 12 proteins that are required for entry of both virus forms. These proteins are conserved in all members of the poxvirus family, suggesting a common entry mechanism.